Cerebral malaria (CM) is defined as an otherwise unexplained coma in a patient with Plasmodium falciparum parasitemia. The condition is common, primarily affects African children less than five years old, and has a large public health impact in endemic areas. Most of the 675,000 malaria deaths each year are from CM; the case fatality rate is 15%, and 30% of survivors have neurological abnormalities at the time of hospital discharge. The mainstay of treatment is intravenous antimalarial drugs and supportive care. No adjunctive therapy has previously been proven effective in decreasing the high rates of mortality and morbidity in this condition. Our long-term goal is to establish feasible therapies that decrease death and disability rates in this vulnerable population. We recently determined that severely increased brain volume in children with CM is strongly associated with death. In survivors, however, brain volumes diminished quickly, without specific treatment. Recognizing that increased brain volume is now a specific therapeutic target, we will perform a randomized, non-blinded controlled clinical trial of two adjunctive therapies: hypertonic saline or early intubation with mechanical ventilation. The first addresses a likely cause of increased brain volume (cytotoxic edema) and the second addresses the likely cause of death (respiratory arrest). We will randomize Malawian children with CM and severely increased brain volumes on screening brain MRI (magnetic resonance imaging) to one of three study arms: usual treatment (elevation of the head of the bed by 30 degrees, antimalarial drugs, and supportive care); usual treatment plus intravenous hypertonic saline; or usual treatment plus early intubation and mechanical ventilation. Our primary outcome will be failure of the first treatment to which the child is assigned or death, whichever comes first. Secondary outcomes include neurological disabilities at hospital discharge and thereafter. We hypothesize that subjects randomized to one or both of our intervention arms will show significantly decreased mortality without a rise in neurological morbidity, compared to those randomized to usual treatment. Simultaneously with our clinical trial, we will evaluate candidate biomarkers of increased brain volume in children with CM. If a biomarker shows internal validity for identifying children with CM with high brain volumes, this will facilitate uptake of our study results into African hospitals where MRI is unavailable. In summary, the proposed research is significant because the therapies used in our intervention arms target an important risk factor for death in children with CM. Should either of the proposed interventions prove to be efficacious, it will be the first time an adjunctive therapy has been shown to decrease death and/or disability rates in these children. With widespread adoption of a favorable intervention into other centers, the public health impact of this devastating neurological infection may finally fall.